Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication

Abstract

Disclosed are compounds of Formula I, including pharmaceutically acceptable salts, pharmaceutical compositions comprising the compounds, methods for making the compounds and their use in inhibiting HIV integrase and treating those infected with HIV or AIDS.

1 . A compound of Formula I or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from hydrogen or alkyl; 
         R 2  is selected from phenyl, pyridinyl, or pyrimidinyl, and is substituted with 0-1 substituent selected from R 6 , R 7 , R 8 , and R 9 , and also substituted with 0-3 substituents selected from cyano, halo, alkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkenyl, cycloalkyl, cyanocycloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, formyl, carboxy, and CH 3 CONHNHCO—; 
         R 3  is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, cyanoalkyl, cycloalkyl, alkenyl, alkoxy, haloalkoxy, phenyl, or benzyl; 
         R 4  is selected from alkyl or haloalkyl; 
         R 5  is alkyl; 
         R 6  is selected from CONR 10 R 11  or (CONR 10 R 11 )alkyl; 
         R 7  is selected from Ar 2 , (Ar 2 )alkyl, (Ar 2 )hydroxyalkyl , (Ar 2 )alkenyl, or (Ar 2 )alkylcarbonyl; 
         R 8  is selected from alkylthio, (Ar 1 )alkylthio, alkylsulfonyl, (Ar 1 )alkylsulfonyl, ((Ar 1 )alkyl)(alkoxycarbonylN═)S, ((Ar 1 )alkyl)(alkoxycarbonylN═)(O)S, or SONR 12 R 13 ; 
         R 9  is NR 14 R 15 ; 
         R 10  is selected from hydrogen, alkyl, cycloalkyl, (Ar 1 )alkyl, (Ar 1 )haloalkyl, ((Ar 1 )CO)alkyl, ((Ar 1 )CH 2 CO)alkyl; 
         R 11  is selected from hydrogen or alkyl; 
         or NR 10 R 11  taken together is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl; 
         R 12  is selected from hydrogen, alkyl, or cycloalkyl; 
         R 13  is selected from hydrogen, alkyl, or cycloalkyl; 
         or NR 12 R 13  taken together is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl; 
         R 14  is selected from hydrogen, alkyl, (Ar 1 )alkyl, (Ar 1 )hydroxyalkyl, (Ar 1 )alkylcarbonyl, or benzyloxycarbonyl; 
         R 15  is selected from hydrogen, alkyl, hydroxyalkyl, (Ar 1 )alkyl, or alkylcarbonyl; 
         Ar 1  is selected from phenyl or pyridinyl and is substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, haloalkoxy, carboxy, and alkoxycarbonyl; and 
         Ar 2  is selected from phenyl or naphthyl and is substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, haloalkoxy, phenyl, and pyridinyl; or Ar 2  is selected from oxazolyl, thiazolyl, imidazolyl, or tetrazolyl, and is substituted with 0-2 substituents selected from halo, (Ar 1 ), and (Ar 1 )alkyl. 
       
     
     
         2 . A compound or salt of  claim 1  wherein R 2  is selected from phenyl, pyridinyl, or pyrimidinyl, and is substituted with 1 R 6  substituent and also substituted with 0-3 substituents selected from cyano, halo, alkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkenyl, cycloalkyl, cyanocycloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, formyl, carboxy, and CH 3 CONHNHCO—. 
     
     
         3 . A compound or salt of  claim 1  wherein R 2  is selected from phenyl, pyridinyl, or pyrimidinyl, and is substituted with 1 R 7  substituent and also substituted with 0-3 substituents selected from cyano, halo, alkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkenyl, cycloalkyl, cyanocycloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, formyl, carboxy, and CH 3 CONHNHCO—. 
     
     
         4 . A compound or salt of  claim 1  wherein R 2  is selected from phenyl, pyridinyl, or pyrimidinyl, and is substituted with 1 R 8  substituent and also substituted with 0-3 substituents selected from cyano, halo, alkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkenyl, cycloalkyl, cyanocycloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, formyl, carboxy, and CH 3 CONHNHCO—. 
     
     
         5 . A compound or salt of  claim 1  wherein R 2  is selected from phenyl, pyridinyl, or pyrimidinyl, and is substituted with 1 R 9  substituent and also substituted with 0-3 substituents selected from cyano, halo, alkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkenyl, cycloalkyl, cyanocycloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, formyl, carboxy, and CH 3 CONHNHCO—. 
     
     
         6 . A compound or salt of  claim 1  wherein R 3  is piperidinyl, gem-disubstituted in the 4-position with 2 substituents selected from cyano, halo, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkenyl, alkoxy, haloalkoxy, CON(R 6 )(R 7 ), phenyl, benzyl, or (alkyl)oxadiazolyl. 
     
     
         7 . A compound or salt of  claim 1  wherein R 10  is selected from hydrogen, alkyl, cycloalkyl, (Ar 1 )alkyl, (Ar 1 )haloalkyl, ((Ar 1 )CO)alkyl, ((Ar 1 )CH 2 CO)alkyl; and R 11  is selected from hydrogen or alkyl. 
     
     
         8 . A compound or salt of  claim 1  wherein NR 10 R 11  taken together is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl. 
     
     
         9 . A compound or salt of  claim 1  wherein R 12  and R 13  are selected from hydrogen, alkyl, or cycloalkyl. 
     
     
         10 . A compound or salt of  claim 1  wherein NR 12 R 13  taken together is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl. 
     
     
         11 . A compound or salt of  claim 1  wherein Ar 2  is selected from phenyl or naphthyl and is substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, haloalkoxy, phenyl, and pyridinyl. 
     
     
         12 . A compound or salt of  claim 1  wherein Ar 2  is selected from oxazolyl, thiazolyl, imidazolyl, or tetrazolyl, and is substituted with 0-2 substituents selected from halo, (Ar 1 ), and (Ar 1 )alkyl. 
     
     
         13 . A composition useful for treating HIV infection comprising a compound or salt of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         14 . The composition of  claim 13  further comprising at least one other agent used for treatment of AIDS or HIV infection selected from nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors. 
     
     
         15 . The composition of  claim 14  wherein the other agent is dolutegravir. 
     
     
         16 . A method for treating HIV infection comprising administering a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, to a patient in need thereof. 
     
     
         17 . The method of  claim 16  further comprising administering at least one other agent used for treatment of AIDS or HIV infection selected from nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors. 
     
     
         18 . The method of  claim 17  wherein the other agent is dolutegravir. 
     
     
         19 . The method of  claim 17  wherein the other agent is administered to the patient prior to, simultaneously with, or subsequently to the compound of  claim 1 .